Influence of Titanium Dioxide Particle Size on the Photostability of the Chemical UV-Filters Butyl Methoxy Dibenzoylmethane and Octocrylene in a Microemulsion

Cosmetics 2014, 1, 128-139; doi:10.3390/cosmetics1020128 OPEN ACCESS cosmetics ISSN 2079-9284 www.mdpi.com/journal/cosmetics Article Influence of Titanium Dioxide Particle Size on the Photostability of the Chemical UV-Filters Butyl Methoxy Dibenzoylmethane and Octocrylene in a Microemulsion Jutta Kockler *, Michael Oelgemöller, Sherryl Robertson and Beverley D. Glass School of Pharmacy and Molecular Sciences, James Cook University, Townsville 4811, QLD, Australia; E-Mails: [email protected] (M.O.); [email protected] (S.R.); [email protected] (B.D.G.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +61-7-4781-3440; Fax: +61-7-4781-5356. Received: 8 May 2014; in revised form: 5 June 2014 / Accepted: 5 June 2014 / Published: 11 June 2014 Abstract: Sunscreen products often contain combinations of ultraviolet (UV)-filters in order to achieve broad spectrum protection from exposure to sunlight. The inclusion of both chemical and physical UV-filters in these products, however, increases the possibility for both photolytic and photocatalytic reactions to occur. This study investigated the effect of titanium dioxide (TiO2) particle size on the photostability of the chemical UV-filters butyl methoxy dibenzoylmethane (BMDM) and octocrylene (OC) formulated in a microemulsion. The International Conference on Harmonisation (ICH) Guideline Q1B for photostability testing of new active substances and medicinal products was applied. BMDM and OC in the microemulsion were irradiated with simulated sunlight in the presence of nano- (<25 nm) and micro-TiO2 (~0.6 μm) and their concentrations determined using a validated high performance liquid chromatography (HPLC) method. For the combination of BMDM and OC, the photodegradation for BMDM was found to be 12% higher in the presence of nano-TiO2 as compared to that of the micro-TiO2. This enhanced photodegradation is attributed to the larger surface area of the nano-TiO2 and the increased generation of reactive oxygen species (ROS). Because of these findings, sunscreen products containing chemical UV-filters and nano-TiO2 should be regarded with caution, due to the potential loss of photoprotection. Cosmetics 2014, 1 129 Keywords: photostability; titanium dioxide; particle size; nano-TiO2; microemulsion; butyl methoxy dibenzoylmethane; octocrylene; high performance liquid chromatography (HPLC) 1. Introduction Sunscreen products often contain a combination of ultraviolet (UV)-filters to achieve broad spectrum UV-protection. TiO2 is a physical filter offering protection from both UVB- (290–320 nm) and UVA I (320–340 nm)-light. Butyl methoxy dibenzoylmethane (BMDM, Figure 1) is a chemical UV-filter, protecting from UVA I- and UVA II (340–400 nm)-light, while octocrylene (OC, Figure 1) is a UVB-filter. Photostability of UV-filters is essential to ensure protection from dangerous health effects such as skin cancer or immunosuppression, caused by excessive exposure to UV-light [1]. Although TiO2 is photostable, some chemical UV-filters such as BMDM are susceptible to photodegradation on UV-irradiation [2]. Photodegradation results in a loss of UV-protection, since most photodegradants show UV-absorption at lower wavelengths than their parent compounds. These photodegradants may also cause allergic skin reactions and other toxic effects. For example, it was shown that exposure of octyl methoxycinnamate to UV-light increased the toxicity to mouse cells [3]. The photodegradants of BMDM also resulted in cytotoxic effects towards the amino acid arginine and photosensitive effects using the local lymphonode assay, a typical in vivo test for skin sensitization [4]. Sunscreen products are listed in the Australian Register of Therapeutic Goods and regarded as over-the-counter (OTC) drugs in the USA and as such, photostability testing as described by the International Conference on Harmonisation (ICH) Guideline Q1B [5], is not mandatory in either of these countries [6,7]. Figure 1. Chemical structures of butyl methoxy dibenzoylmethane (BMDM) and octocrylene (OC). TiO2 is a widely used in sunscreen products and often in combination with chemical UV-filters [6,7]. Two crystalline forms, anatase and rutile, are available in different particle sizes, with particles under 100 nm classified as nanoparticles, and those larger particles as microparticles. Micro-sized TiO2 appears white on the skin and is thus not very popular with consumers, while nano-sized TiO2 is nowadays more often used because of its transparency and improved aesthetic appearance [8]. However, TiO2 has the potential to compromise the photostability of chemical UV-filters in combination sunscreen products. In particular, it has been shown that TiO2 increases their photodegradation due to its photocatalytic properties and ability to generate reactive oxygen species Cosmetics 2014, 1 130 (ROS) [2,9]. These results are not surprising as TiO2 is often used as a photocatalyst in water treatment, to induce the photodegradation of organic pollutants [10]. To address this issue TiO2 used for sunscreen products is often coated, for example with silica, dimethicone or aluminium hydroxide [11–13]. Uncoated TiO2 material for the use in sunscreen products is also available on the market [14–16] and still used, which may be due to potential cost implications of using the coated material [14]. Sunscreen manufacturers are also not required to use only the coated material or even state on the label whether or not coated TiO2 was employed in the final formulation [6,7,17]. TiO2 extracted from several commercially available sunscreen products caused the photodegradation of azur B and the oxidation of α-terpinene, attributed to the generation of singlet oxygen [11] and resulted in significant cellular damage of cultured cell lines [18]. This is possibly due to the presence of uncoated TiO2 in the formulation or that the integrity of the coating may have been compromised. In Europe, sunscreen products containing nanomaterials are required to be clearly labeled with the word “nano” after the name of the ingredient [17], while in Australia and the USA this is not a requirement [6,7]. Despite this labeling requirement in Europe, the photoreactivity of different-sized TiO2 particles has thus far not been compared and therefore its effects on the stability of other ingredients in the sunscreen are unknown. The current study was therefore undertaken to examine the effect of TiO2 particle size (nano- and micro-TiO2) and coating (non- and silica coated TiO2) on the photostability of BMDM and OC. Due to lack of available photostability protocols for sunscreens, the internationally recognized ICH Guideline Q1B was followed. This is appropriate, as the complete exposure dose recommended in these guidelines (21 MJ/m2) is in the same range than the daily solar exposure in Australia in summer (20–28 MJ/m2) [19]. Previous photostability studies of UV-filters undertaken used an equivalent UVA irradiation dose of 90 [20,21] or 60 [22,23] min of sunshine on the French Riviera (Nice) in summer at noon or a full day in Scandinavia [24,25]. Equivalents of standard erythemal doses (SED) to solar radiation at midsummer noon in central Europe [26] or of minimal erythemal doses (MED) of half-day solar emission close to the equator [27] have also been reported. 2. Experimental Section 2.1. Materials UV-filters, 4-tert-butyl-4’-methoxy dibenzoylmethane (butyl methoxy dibenzoylmethane, Eusolex® 9020), 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (octocrylene, Eusolex® OCR) and the silica-coated titanium dioxide (Eusolex® T-AVO; 100% rutile, particle size ~119 nm) were purchased from Merck (Darmstadt, Germany). Anatase nano- (99.7% trace metals basis, particle size <25 nm) and micro-TiO2 (≥99% trace metals basis, particle size ~0.6 μm) were purchased from Sigma Aldrich (St. Louis, MI, USA). High performance liquid chromatography (HPLC)-grade methanol was obtained from RCI Labscan (Bankok, Thailand) and reverse osmosis water was prepared with a Millipore® Elix 10 from Millipore SAS (Molsheim, France). Xanthan gum and Mygliol® 812 (caprylic/capric triglycerides) were acquired from PCCA (Houston, TX, USA), glycerol oleate from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan) and oleth-20 (Brij® 98) from Acros Organics (Geel, Belgium). Other chemicals and solvents of reagent grade were used without further purification. Cosmetics 2014, 1 131 2.2. Methods 2.2.1. Microemulsion Preparation An oil in water (O/W) microemulsion was prepared according to a procedure described by Montenegro et al. [28], using the phase inversion temperature (PIT) method [29]. The component oil and water phases were however modified and a thickener was added to achieve an appropriate viscosity for a sunscreen product. The oil, Mygliol® 812 (10.0% w/w), glycerol oleate (4.4% w/w), oleth-20 (11.0% w/w), containing BMDM (1.0% w/w) and OC (1.5% w/w) and water phases were heated to 85–90 °C, combined and then cooled to 40 °C, after the formation of the microemulsion. Phenoxyethanol (1.0% w/w), TiO2 (2.0% w/w) and xanthan gum (0.6% w/w) were then added with constant stirring and the final weight adjusted with water to 10.0 g. The oil soluble UV-filters BMDM and OC were dissolved in the internal phase, while TiO2 was evenly dispersed in the external phase. 2.2.2. Photostability Studies Irradiations of UV-filters in the microemulsion were undertaken in a SunTest XLS+(I) solar simulator from Atlas Material Testing Technology GmbH (Linsengericht, Germany) according to the ICH Guideline Q1B [5]. The solar simulator was equipped with a xenon arc lamp (2.2 kVA) and a UV-glass-filter D65, which transmits wavelengths above 290 nm and is recognised as the internationally standard for outdoor daylight [5]. About 20 mg (accurately weighed) of the microemulsion was evenly spread onto a glass surface of 10 cm2 and maintained at <40 °C during irradiation at 400 W/m2 for 14.6 h (1.2 million lux hours), which is equivalent to 21 MJ/m2.

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